Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
  • A61K31/80—Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
  • F04C—ROTARY-PISTON, OR OSCILLATING-PISTON, POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; ROTARY-PISTON, OR OSCILLATING-PISTON, POSITIVE-DISPLACEMENT PUMPS
  • F04C2270/00—Control; Monitoring or safety arrangements
  • F04C2270/04—Force
  • F04C2270/042—Force radial
  • F04C2270/0421—Controlled or regulated

Definitions

• This invention relates to moisture-curable sealants for sealing biological tissue.
• Tissue sealants are typically used to stop bleeding during vascular or liver surgery, eliminate air leaks in the lungs, and to prevent adhesions.
• sealants used for this purpose include fibrin products, polyethylene glycol products, and albumin- based products.
• the tissue sealant consists of two distinct components that are mixed together just prior to application to tissue to cause a rapid, irreversible chemical reaction. This reaction transforms the mixture from a low viscosity liquid into an elastic solid that coats the target tissue.
• the sealants are designed to degrade within a set period of time that typically ranges from days to weeks.
• One problem with such two- part sealants, however, is that the rapid cure times can cause the sealant applicator to clog.
• a tissue sealant includes the reaction product of (a) a polyol; (b) a polyisocyanate; and (c) an alkoxy silane.
• the alkoxy silane has the formula: (R ⁇ R 3 )- Si-CH 2 -Z where (i) Z is an -OH, -SH, -NCO, or -NHR 4 group, where R 4 is hydrogen, an alkyl group, or an aryl group; and (ii) each R 1 , R 2 , and R 3 , independently, is H, an alkoxy group, an alkyl group, a heteroalkyl group other than an alkoxy group, an aryl group, or a heteroaryl group, with the proviso that at least two of R 1 , R 2 , and R 3 are alkoxy groups.
• the relative amounts of the polyol, polyisocyanate, and alkoxy silane are selected such that the reaction product includes free isocyanate groups.
• the tissue sealant is moisture-cur
• alkyl includes straight chain, branched, and cyclic alkyl groups.
• the tissue sealant also includes an isocyanate-functional organosilane.
• the isocyanate-functional organosilane has at least one free isocyanate group and at least one terminal silane group having the formula: (R 5 R 6 R 7 )-Si- where each R 5 , R 6 , and R 7 , independently, is H, an alkoxy group, an alkyl group, a heteroalkyl group other than an alkoxy group, an aryl group, or a heteroaryl group.
• R 1 , R 2 , and R 3 are Ci-C 6 alkoxy groups. In other embodiments, each of R 1 , R 2 , and R 3 is a Ci-C 6 alkoxy group.
• suitable Z groups include an -NHR 4 group, e.g., where R 4 is a phenyl group.
• the isocyanate-functional organosilane has a molecular weight no greater than 500 g/mole, while in other embodiments it has a molecular weight no greater than 300 g/mole.
• At least one of R 5 , R 6 , and R 7 of the isocyanate-functional organosilane is a Ci-C 6 alkoxy group. In other embodiments, each of R 5 , R 6 , and R 7 of the isocyanate-functional organosilane is a Ci-C 6 alkoxy group.
• a suitable isocyanate-functional organosilane is a compound having the formula: (R 5 R 6 R 7 )-Si-R 8 -NCO where R 8 is a Ci-Cio alkyl group.
• the polyol may be selected from the group consisting of polyether polyols, polyester polyols, co-polyester polyether polyols, alkoxylated glycerol derivatives, and combinations thereof.
• the polyisocyanate may be selected from the group consisting of lysine diisocyanate and derivatives thereof, lysine triisocyanate and derivatives thereof, and combinations thereof.
• the tissue sealant includes the reaction product of the alkoxy silane, the polyisocyanate, and at least two different polyols. Two polyols are "different" from each other if they have different molecular weights and/or chemical structures.
• the tissue sealant can also include at least one reagent selected from the group consisting of solvents, diluents, coagulents, catalysts, and combinations thereof.
• the tissue sealant can also include a colorant such as beta-carotene.
• the sealant is applied to a tissue surface, and cured in the presence of moisture associated with the tissue to seal the tissue surface. Because the sealant is a one-component composition (i.e. it includes one active molecule that moisture cures upon application to tissue), it is not necessary to mix two components prior to tissue application, thereby simplifying application from the user's perspective and avoiding the applicator clogging problems associated with two-component tissue sealants.
• the sealant is stable in the absence of moisture, thus facilitating storage.
• the sealant also adheres well to biological tissue, particularly when the isocyanate-functional organosilane is included, and has good mechanical properties.
• the tissue sealant includes the reaction product of a polyol, a polyisocyanate, and an alkoxy silane.
• the stoichiometry of the reactants is selected such that the resulting reaction product has free (i.e. unreacted) isocyanate groups.
• the alkoxy silane has the formula: (R 1 R 2 R 3 )-Si-CH 2 -Z where (i) Z is an -OH, -SH, -NCO, or -NHR 4 group.
• R 4 is a hydrogen, an alkyl group (e.g., a Ci-C 6 alkyl group), or an aryl group (e.g., having at least one ring such as a phenyl group).
• Each R 1 , R 2 , and R 3 is H, an alkoxy group (e.g., a Ci-C 6 alkoxy group), an alkyl group (e.g., a Ci-C 6 alkyl group), a heteroalkyl group other than an alkoxy group (e.g., an alkyl amido or amido group), an aryl group (e.g., a phenyl group), or a heteroaryl group (e.g., a pyrrolyl, furyl, or pyridinyl group), with the proviso that at least two of R 1 , R 2 , and R 3 are alkoxy groups.
• the alkyl groups may be straight chain, branched, or cyclic alkyl groups.
• the polyol includes at least two hydroxyl groups available for reaction.
• suitable polyols include polyether polyols, polyester polyols, co-polyester polyols, and alkoxylated glycerol derivatives (e.g., glycerol ethoxylate).
• polyether polyols include polyethylene and polypropylene glycols.
• polyester polyols include polycaprolactone and polylactide diols.
• Typical polyols have molecular weights less than 10,000. In some embodiments, the polyol may have a molecular less than 5,000 or less than 2,000. Mixtures of two or more different polyols can be used as well. For example, diols and triols can be used in combination with each other.
• the polyisocyanate includes at least two isocyanate groups available for reaction.
• the polyisocyanate may be selected from the group consisting of lysine diisocyanate and derivatives thereof, lysine triisocyanate and derivatives thereof, and combinations thereof.
• the sealant may also include an isocyanate-functional organosilane.
• the isocyanate-functional organosilane has at least one free isocyanate group and at least one terminal silane group having the formula: (R 5 R 6 R 7 )-Si- where each R 5 , R 6 , and R 7 , independently, is H, an alkoxy group (e.g., a Ci-C 6 alkoxy group), an alkyl group (e.g., a Ci-C 6 alkyl group), a heteroalkyl group other than an alkoxy group (e.g., an alkyl amido or amido group), an aryl group (e.g., a phenyl group), or a heteroaryl group (e.g., a pyrrolyl, furyl, or pyridinyl group).
• an alkoxy group e.g., a Ci-C 6 alkoxy group
• an alkyl group e.g., a Ci
• the isocyanate-functional organosilane is included in an amount of up to 15% by weight, based upon the weight of the composition. In some embodiments, it is included in an amount of up to 8% by weight, while in other embodiments the amount is up to 3%) by weight.
• the sealants may further contain one or more reagents selected from the group consisting of solvents, diluents, coagulents, catalysts, and combinations thereof.
• the reagents preferably are inert towards the polyol, polyisocyanate, alkoxy silane, and isocyanate-functional organosilane, and thus do not interfere with the reaction among these compounds.
• Suitable catalysts include tertiary amines (e.g., aliphatic tertiary amines), organometallic compounds (e.g., bismuth salts and zirconium chelates), Bronsted acids, and protonic acids (e.g., sulfuric or hydrochloric acid).
• organometallic compounds e.g., bismuth salts and zirconium chelates
• Bronsted acids e.g., sulfuric or hydrochloric acid
• protonic acids e.g., sulfuric or hydrochloric acid.
• useful coagulents include calcium salts.
• the solvents and diluents may be used to modify the rheology of the sealant.
• suitable solvents include dimethylsulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran (THF), glyme, and combinations thereof.
• suitable non-volatile diluents include dimethylsulfoxide (DMSO), propylene carbonate, diglyme, polyethylene glycol diacetates, polyethylene glycol dicarbonates, dimethylisosorbide, ethyl pyruvate, triacetin, triethylene glycol, and combinations thereof.
• suitable volatile diluents include hydrocarbons, perfluoroalkanes, hydrofluoroalkanes, carbon dioxide, and combinations thereof.
• a single reagent can perform multiple roles.
• DMSO can function as both a solvent and a non-volatile diluent.
• the sealants may also include one or more stabilizers. Examples include antioxidants (e.g., BHT and BHA), water scavengers (e.g., acyl and aryl halides, and anhydrides), Bronsted acids, and the like. Bronsted acids may also be used as catalysts.
• the sealant may also include a colorant to help a surgeon visualize the sealant during application to biological tissue.
• a colorant is beta- carotene.
• the sealants are typically prepared by reacting the polyol, polyisocyanate, and alkoxy silane together, either in a single step reaction, in which reactants are combined together in a "single pot” reaction, or a multi-step reaction, in which the reactants are reacted sequentially.
• the resulting reaction product is then combined with the isocyanate-functional organosilane and any of the aforementioned ingredients.
• Porcine small intestine was acquired from Tissue Source (Indiana) and stored at - 10°C prior to use.
• the intestine is washed thoroughly with cold water prior to testing. Sections of approximately 24 cm are prepared for use in bond testing; the sections are stored at 37°C and 100% relative humidity prior to application of the sealant. Then at ambient conditions, the intestine sample is marked off in 3 sections (thirds) marked as “dry”, “damp”, and “wet”; the entire sample is then blotted dry. A sponge is soaked in phosphate buffered saline (PBS) and then squeezed over the "damp” and 'wet" sections of the sample - subsequently the "damp" section is lightly blotted with a towel. At this point, sealant is applied to each of the sample sections via syringe - approximately 0.1 cc is used per application. The sealant is then allowed to cure for 20 minutes at room temperature and ambient relative humidity prior to testing. Each of the sealant strips is manipulated with a gloved finger - scoring is shown in the table below; data are reported as averages of 3 runs.
• the sealant is easily removed with little to no manipulation or
• the sealant is slightly adhered, peels off the surface with
• the sealant is slightly well adhered, requires some removal in z
• the test is conducted following ASTM F 2392-04, Standard Test Method for Burst Strength of Surgical Sealants.
• Porcine skin is acquired from Arthur Medical (Minnesota) and stored at -10°C prior to use. The skin is cut into 31 ⁇ 2 cm x 31 ⁇ 2 cm squares and stored at 37°C and 100% relative humidity prior to application of the sealant.
• Ethyl pyruvate ( 97.5%), phenylaminomethyl triethoxysilane ( 97 %), dimethyl sulfoxide (99.9%) and lysine (ethyl ester) di-isocyanate (LDI, 99.2%), and N-phenylaminomethyl triethoxysilane (99%) were received from Sigma- Aldrich Fine Chemicals and used as received.
• Sulfuric acid (99.999%), isocyanatopropyl triethoxysilane ( 95%>), and methyl acetate ( 99.5%>) were purchased from Aldrich Chemical Co and used as received.
• Example 2 Synthesis of sealant with no residual isocyanate groups and no isocyanate-functional silane for comparative purposes
• phenylaminomethyl triethoxysilane (40.7 g, 151.4 mmol amine) was added under nitrogen while maintaining temperature at 80°C.
• the reaction was allowed to continue until infra-red spectroscopy (at a wavelength of 2265 cm "1 ) showed that all of the isocyanate groups had been consumed.
• 43.6 g ethyl pyruvate was added with stirring, followed by 0.01 g sulfuric acid.
• the resulting sealant was initially stored at 4°C.
• Example 3 Synthesis of sealant with free isocyanate groups Following the LDI-polymer reaction in Example 1, phenylaminomethyl triethoxysilane was added in a less-than-stoichiometric amount relative to the isocyanate groups present; for example 17.5 g (65.1 mmol). This addition was done under nitrogen while maintaining temperature at 80°C. The reaction was allowed to continue until infrared spectroscopy showed that the isocyanate concentration (2265 cm "1 ) was not changing substantially over time. Ethyl pyruvate and sulfuric acid were added as in Example 2. Titration against dibutyl amine and acid demonstrated the presence of residual isocyanate groups in the material.
• a sealant was synthesized as in examples 3. Following addition of the ethyl pyruvate, isocyanatopropyl triethoxysilane was added in amounts ranging from 4.8 g (19.4 mmol NCO) to 11.4 g (46.2 mmol NCO).

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